My long-term objective is to elucidate the molecular mechanisms of vascular smooth muscle cell (VSMC) development and differentiation in the zebrafish. Smooth muscle proliferation is thought to play a major role in the development of atherosclerosis and restenosis that occurs in patients treated by angioplasty. Therefore, an understanding of the mechanisms of VSMC recruitment and differentiation is critical for designing safe and effective therapeutic strategies to treat these conditions. However, very little is known regarding the origin of VSMC and their proliferation. This is, at least in part, the result of the difficulties associated with experimental and genetic analysis of this early differentiating, essential tissue in most vertebrate organisms. The genetic tractability of the zebrafish, combined with the optical clarity and experimental accessibility of its embryos makes this an ideal organism for these studies. The specific goals of this proposal are to (1) characterize the developmental progression of VSMC acquisition in wild type and mutant zebrafish and (2) to develop transgenic tools for experimental analysis of VSMC formation and differentiation. It is our hope that our studies will lead to a better understanding of vascular smooth muscle recruitment and differentiation and eventually to the development of better therapeutic strategies to treat atherosclerosis and restenosis.